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Nutraceuticals have been described as phytocomplexes when derived from foods of plant origin or a pool of secondary metabolites when derived from foods of animal origin, which are concentrated and administered in an appropriate form and can promote beneficial health effects in the prevention/treatment of diseases. Considering that pharmaceutical medications can cause side effects, there is a growing interest in using nutraceuticals as an adjuvant therapeutic tool for several disorders involving autonomic dysfunction, such as obesity, atherosclerosis and other cardiometabolic diseases. This review summarizes and discusses the evidence from the literature on the effects of various nutraceuticals on autonomic control, addressing the gut microbiota modulation, production of secondary metabolites from bioactive compounds, and improvement of physical and chemical properties of cell membranes. Additionally, the safety of nutraceuticals and prospects are discussed. Probiotics, resveratrol, quercetin, curcumin, nitrate, inositol, L-carnosine, and n-3 polyunsaturated fatty acids (n-3 PUFAs) are among the nutraceuticals most studied to improve autonomic dysfunction in experimental animal models and clinical trials. Further human studies are needed to elucidate the effects of nutraceuticals formulated of multitarget compounds and their underlying mechanisms of action, which could benefit conditions involving autonomic dysfunction.
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This study aimed to evaluate the functional, technological, and sensory aspects of mangaba (Hancornia speciosa Gomes) fruit pulp fermented with the probiotic Lacticaseibacillus casei 01 (LC1) during refrigerated storage (7 °C, 28 days). The effects of the fermented mangaba pulp on the modulation of the intestinal microbiota of healthy vegan adults were also assessed. Mangaba pulp allowed high viability of LC1 during storage and after simulated gastrointestinal conditions (≥7 log CFU/g). The fermented mangaba pulp showed lower pH and total soluble solids, and higher titratable acidity, and concentrations of lactic, acetic, citric, and propionic acids during storage compared to non-fermented pulp. Also, it presented a higher concentration of bioaccessible phenolics and volatiles, and improved sensory properties (yellow color, brightness, fresh appearance, and typical aroma and flavor). Fermented mangaba pulp added to in vitro cultured colonic microbiota of vegan adults decreased the pH values and concentrations of maltose, glucose, and citric acid while increasing rhamnose and phenolic contents. Fermented mangaba pulp promoted increases in the abundance of Dorea, Romboutsia, Faecalibacterium, Lachnospira, and Lachnospiraceae ND3007 genera and positively impacted the microbial diversity. Findings indicate that mangaba pulp fermented with LC1 has improved chemical composition and functionality, inducing changes in the colonic microbiota of vegan adults associated with potential benefits for human health.
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Fermentación , Microbioma Gastrointestinal , Lacticaseibacillus casei , Humanos , Microbioma Gastrointestinal/fisiología , Lacticaseibacillus casei/metabolismo , Adulto , Gusto , Probióticos , Masculino , Concentración de Iones de Hidrógeno , Frutas/microbiología , Frutas/química , Colon/microbiología , Colon/metabolismo , Adulto Joven , FemeninoRESUMEN
Supplementation with probiotics has emerged as a promising therapeutic tool to manage metabolic diseases. We investigated the effects of a mix of Bifidobacterium animalis subsp. lactis LA804 and Lactobacillus gasseri LA806 on high-fat (HF) diet -induced metabolic disease in mice. Supplementation with the probiotic mix in HF diet-fed mice (HF-Pr2) reduced weight and fat mass gains, decreased hepatic lipid accumulation, and lowered plasma triglyceride peak during an oral lipid tolerance test. At the molecular level, the probiotic mix protected against HF-induced rise in mRNA levels of genes related to lipid uptake, metabolism, and storage in the liver and white adipose tissues, and strongly decreased mRNA levels of genes related to inflammation in the white adipose tissue and to oxidative stress in the liver. Regarding intestinal homeostasis, the probiotic mix did not prevent HF-induced gut permeability but slightly modified microbiota composition without correcting the dysbiosis induced by the HF diet. Probiotic supplementation also modified the cecal bile acid (BA) profile, leading to an increase in the Farnesoid-X-Receptor (FXR) antagonist/agonist ratio between BA species. In agreement, HF-Pr2 mice exhibited a strong inhibition of FXR signaling pathway in the ileum, which was associated with lipid metabolism protection. This is consistent with recent reports proposing that inhibition of intestinal FXR activity could be a potent mechanism to overcome metabolic disorders. Altogether, our results demonstrate that the probiotic mix evaluated, when administered preventively to HF diet-fed mice could limit obesity and associated lipid metabolism disorders, likely through the inhibition of FXR signaling in the intestinal tract.
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Microbioma Gastrointestinal , Probióticos , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Metabolismo de los Lípidos , Aumento de Peso , Probióticos/farmacología , Probióticos/uso terapéutico , Hígado/metabolismo , Triglicéridos , ARN Mensajero/metabolismo , ARN Mensajero/farmacología , Ratones Endogámicos C57BL , Ácidos y Sales Biliares/metabolismoRESUMEN
BACKGROUND: Obesity is a well-known risk factor for cancer. We have previously reported the role of adipose-tissue-derived mesenchymal stem cells from obese individuals (ob-ASC) in the promotion of pathogenic Th17 cells and immune check point (ICP) upregulation. Thus, we postulated herein that this mechanism could contribute to breast cancer (BC) aggressiveness. METHODS: Conditioning medium (CM) from mitogen-activated ob-ASC and immune cell co-cultures were added to two human breast cancer cell line (BCCL) cultures. Expressions of pro-inflammatory cytokines, angiogenesis markers, metalloproteinases, and PD-L1 (a major ICP) were measured at the mRNA and/or protein levels. BCCL migration was explored in wound healing assays. Anti-cytokine neutralizing antibodies (Ab) were added to co-cultures. RESULTS: CM from ob-ASC/MNC co-cultures increased IL-1ß, IL-8, IL-6, VEGF-A, MMP-9, and PD-L1 expressions in both BCCLs and accelerated their migration. The use of Abs demonstrated differential effects for IL-17A and IFNγ on BCCL pro-inflammatory cytokine over-expression or PD-L1 upregulation, respectively, but potentiating effects on BCCL migration. Finally, co-cultures with ob-ASC, but not lean ASC, enhanced PD-L1 expression. CONCLUSIONS: Our results demonstrate increased inflammation and ICP markers and accelerated BCCL migration following the activation of pathogenic Th17 cells by ob-ASC, which could represent a new mechanism linking obesity with BC progression.
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Chronic kidney disease (CKD) is associated with osteosarcopenia, and because a physical decline in patients correlates with an increased risk of morbidity, an improvement of the musculoskeletal system is expected to improve morbi-mortality. We recently uncovered that the intestinal hormone Fibroblast Growth Factor 19 (FGF19) is able to promote skeletal muscle mass and strength in rodent models, in addition to its capacity to improve glucose homeostasis. Here, we tested the effects of a treatment with recombinant human FGF19 in a CKD mouse model, which associates sarcopenia and metabolic disorders. In 5/6 nephrectomized (5/6Nx) mice, subcutaneous FGF19 injection (0.1 mg/kg) during 18 days increased skeletal muscle fiber size independently of food intake and weight gain, associated with decreased gene expression of myostatin. Furthermore, FGF19 treatment attenuated glucose intolerance and reduced hepatic expression of gluconeogenic genes in uremic mice. Importantly, the treatment also decreased gene expression of liver inflammatory markers in CKD mice. Therefore, our results suggest that FGF19 may represent a novel interesting therapeutic strategy for a global improvement of sarcopenia and metabolic complications in CKD.
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Factores de Crecimiento de Fibroblastos , Insuficiencia Renal Crónica , Sarcopenia , Animales , Humanos , Ratones , Factores de Crecimiento de Fibroblastos/farmacología , Inflamación/patología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Insuficiencia Renal Crónica/complicaciones , Sarcopenia/patologíaRESUMEN
Despite major recent therapeutic advances, stroke remains a leading cause of disability and death. Consequently, new therapeutic targets need to be found to improve stroke outcome. The deleterious role of gut microbiota alteration (often mentioned as "dysbiosis") on cardiovascular diseases, including stroke and its risk factors, has been increasingly recognized. Gut microbiota metabolites, such as trimethylamine-N-oxide, short chain fatty acids and tryptophan, play a key role. Evidence of a link between alteration of the gut microbiota and cardiovascular risk factors exists, with a possible causality link supported by several preclinical studies. Gut microbiota alteration also seems to be implicated at the acute phase of stroke, with observational studies showing more non-neurological complications, higher infarct size and worse clinical outcome in stroke patients with altered microbiota. Microbiota targeted strategies have been developed, including prebiotics/probiotics, fecal microbiota transplantation, short chain fatty acid and trimethylamine-N-oxide inhibitors. Research teams have been using different time windows and end-points for their studies, with various results. Considering the available evidence, it is believed that studies focusing on microbiota-targeted strategies in association with conventional stroke care should be conducted. Such strategies should be considered according to three therapeutic time windows: first, at the pre-stroke (primary prevention) or post-stroke (secondary prevention) phases, to enhance the control of cardiovascular risk factors; secondly, at the acute phase of stroke, to limit the infarct size and the systemic complications and enhance the overall clinical outcome; thirdly, at the subacute phase of stroke, to prevent stroke recurrence and promote neurological recovery.
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The adaptive response to overfeeding is associated with profound modifications of gene expression in adipose tissue to support lipid storage and weight gain. The objective of this study was to assess in healthy lean men whether a supplementation with polyphenols could interact with these molecular adaptations. Abdominal subcutaneous adipose tissue biopsies were sampled from 42 subjects participating to an overfeeding protocol providing an excess of 50% of their total energy expenditure for 31 days, and who were supplemented with 2 g/day of grape polyphenols or a placebo. Gene expression profiling was performed by RNA sequencing. Overfeeding led to a modification of the expression of 163 and 352 genes in the placebo and polyphenol groups, respectively. The GO functions of these genes were mostly involved in lipid metabolism, followed by genes involved in adipose tissue remodeling and expansion. In response to overfeeding, 812 genes were differentially regulated between groups. Among them, a set of 41 genes were related to angiogenesis and were down-regulated in the polyphenol group. Immunohistochemistry targeting PECAM1, as endothelial cell marker, confirmed reduced angiogenesis in this group. Finally, quercetin and isorhamnetin, two polyphenol species enriched in the plasma of the volunteers submitted to the polyphenols, were found to inhibit human umbilical vein endothelial cells migration in vitro. Polyphenol supplementation do not prevent the regulation of genes related to lipid metabolism in human adipose tissue during overfeeding, but impact the angiogenesis pathways. This may potentially contribute to a protection against adipose tissue expansion during dynamic phase of weight gain.
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Vitis , Masculino , Humanos , Células Endoteliales/metabolismo , Tejido Adiposo/metabolismo , Obesidad/metabolismo , Aumento de Peso/fisiología , Suplementos Dietéticos , Polifenoles/farmacología , Polifenoles/metabolismoRESUMEN
The intestinal microbiota is known to influence postnatal growth. We previously found that a strain of Lactiplantibacillus plantarum (strain LpWJL) buffers the adverse effects of chronic undernutrition on the growth of juvenile germ-free mice. Here, we report that LpWJL sustains the postnatal growth of malnourished conventional animals and supports both insulin-like growth factor-1 (IGF-1) and insulin production and activity. We have identified cell walls isolated from LpWJL, as well as muramyl dipeptide and mifamurtide, as sufficient cues to stimulate animal growth despite undernutrition. Further, we found that NOD2 is necessary in intestinal epithelial cells for LpWJL-mediated IGF-1 production and for postnatal growth promotion in malnourished conventional animals. These findings indicate that, coupled with renutrition, bacteria cell walls or purified NOD2 ligands have the potential to alleviate stunting.
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Microbioma Gastrointestinal , Crecimiento , Intestinos , Lactobacillaceae , Desnutrición , Proteína Adaptadora de Señalización NOD2 , Animales , Ratones , Pared Celular/química , Células Epiteliales/microbiología , Células Epiteliales/fisiología , Microbioma Gastrointestinal/fisiología , Vida Libre de Gérmenes , Trastornos del Crecimiento/fisiopatología , Trastornos del Crecimiento/terapia , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/fisiología , Intestinos/microbiología , Intestinos/fisiología , Lactobacillaceae/fisiología , Desnutrición/fisiopatología , Desnutrición/terapia , Proteína Adaptadora de Señalización NOD2/metabolismo , Crecimiento/efectos de los fármacos , Crecimiento/fisiología , Acetilmuramil-Alanil-Isoglutamina/farmacología , Acetilmuramil-Alanil-Isoglutamina/uso terapéuticoRESUMEN
Introduction and aims: Dietary polyphenols have long been associated with health benefits, including the prevention of obesity and related chronic diseases. Overfeeding was shown to rapidly induce weight gain and fat mass, associated with mild insulin resistance in humans, and thus represents a suitable model of the metabolic complications resulting from obesity. We studied the effects of a polyphenol-rich grape extract supplementation on the plasma metabolome during an overfeeding intervention in adults, in two randomized parallel controlled clinical trials. Methods: Blood plasma samples from 40 normal weight to overweight male adults, submitted to a 31-day overfeeding (additional 50% of energy requirement by a high calorie-high fructose diet), given either 2 g/day grape polyphenol extract or a placebo at 0, 15, 21, and 31 days were analyzed (Lyon study). Samples from a similarly designed trial on females (20 subjects) were collected in parallel (Lausanne study). Nuclear magnetic resonance (NMR)-based metabolomics was conducted to characterize metabolome changes induced by overfeeding and associated effects from polyphenol supplementation. The clinical trials are registered under the numbers NCT02145780 and NCT02225457 at ClinicalTrials.gov. Results: Changes in plasma levels of many metabolic markers, including branched chain amino acids (BCAA), ketone bodies and glucose in both placebo as well as upon polyphenol intervention were identified in the Lyon study. Polyphenol supplementation counterbalanced levels of BCAA found to be induced by overfeeding. These results were further corroborated in the Lausanne female study. Conclusion: Administration of grape polyphenol-rich extract over 1 month period was associated with a protective metabolic effect against overfeeding in adults.
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[This corrects the article DOI: 10.1371/journal.pone.0263479.].
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Two randomized placebo-controlled double-blind paralleled trials (42 men in Lyon, 19 women in Lausanne) were designed to test 2 g/day of a grape polyphenol extract during 31 days of high calorie-high fructose overfeeding. Hyperinsulinemic-euglycemic clamps and test meals with [1,1,1-13C3]-triolein were performed before and at the end of the intervention. Changes in body composition were assessed by dual-energy X-ray absorptiometry (DEXA). Fat volumes of the abdominal region and liver fat content were determined in men only, using 3D-magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) at 3T. Adipocyte's size was measured in subcutaneous fat biopsies. Bodyweight and fat mass increased during overfeeding, in men and in women. While whole body insulin sensitivity did not change, homeostasis model assessment of insulin resistance (HOMA-IR) and the hepatic insulin resistance index (HIR) increased during overfeeding. Liver fat increased in men. However, grape polyphenol supplementation did not modify the metabolic and anthropometric parameters or counteract the changes during overfeeding, neither in men nor in women. Polyphenol intake was associated with a reduction in adipocyte size in women femoral fat. Grape polyphenol supplementation did not counteract the moderated metabolic alterations induced by one month of high calorie-high fructose overfeeding in men and women. The clinical trials are registered under the numbers NCT02145780 and NCT02225457 at ClinicalTrials.gov and available at https://clinicaltrials.gov/ct2/show/NCT02145780 and https://clinicaltrials.gov/ct2/show/NCT02225457.
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BACKGROUND & AIMS: Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions; however, whether MAM dysfunction plays a causal role in hepatic insulin resistance and steatosis is not clear. Thus, we aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment. METHODS: We analyzed hepatic ER-mitochondria interactions and calcium exchange in a time-dependent and reversible manner in mice with diet-induced obesity. Additionally, we used recombinant adenovirus to express a specific organelle spacer or linker in mouse livers, to determine the causal impact of MAM dysfunction on hepatic metabolic alterations. RESULTS: Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in mice with diet-induced obesity. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks' overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type 2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index. CONCLUSIONS: ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could help to restore metabolic homeostasis. LAY SUMMARY: The literature suggests that interactions between the endoplasmic reticulum and mitochondria could play a role in hepatic insulin resistance and steatosis during chronic obesity. In the present study, we reappraised the time-dependent regulation of hepatic endoplasmic reticulum-mitochondria interactions and calcium exchange, investigating reversibility and causality, in mice with diet-induced obesity. We also assessed the relevance of our findings to humans. We show that organelle miscommunication is an early causal trigger of hepatic insulin resistance and steatosis that can be improved by nutritional strategies.
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Diabetes Mellitus Tipo 2 , Hígado Graso , Resistencia a la Insulina , Hepatopatías , Animales , Calcio/metabolismo , Comunicación , Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplásmico/metabolismo , Hígado Graso/etiología , Hígado Graso/metabolismo , Glucosa/metabolismo , Humanos , Hígado/metabolismo , Hepatopatías/metabolismo , Ratones , Mitocondrias/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Factores de Transcripción/metabolismoRESUMEN
As blood-derived miRNAs (c-miRNAs) are modulated by exercise and nutrition, we postulated that they might be used to monitor the effects of a lifestyle intervention (LI) to prevent diabetes development. To challenge this hypothesis, obese Asian Indian pre-diabetic patients were submitted to diet modifications and physical activity for 4 months (LI group) and compared to a control group which was given recommendations only. We have considered 2 periods of time to analyze the data, i.e.; a first one to study the response to the intervention (4 months), and a second one post-intervention (8 months). At basal, 4 months and 8 months post-intervention the levels of 17 c-miRNAs were quantified, selected either for their relevance to the pathology or because they are known to be modulated by physical activity or diet. Their variations were correlated with variations of 25 metabolic and anthropometric parameters and cytokines. As expected, fasting-glycaemia, insulin-sensitivity, levels of exercise- and obesity-induced cytokines were ameliorated after 4 months. In addition, the levels of 4 miRNAs (i.e.; miR-128-3p, miR-374a-5p, miR-221-3p, and miR-133a-3p) were changed only in the LI group and were correlated with metabolic improvement (insulin sensitivity, cytokine levels, waist circumference and systolic blood pressure). However, 8 months post-intervention almost all ameliorated metabolic parameters declined indicating that the volunteers did not continue the protocol on their own. Surprisingly, the LI positive effects on c-miRNA levels were still detected, and were even more pronounced 8 months post-intervention. In parallel, MCP-1, involved in tissue infiltration by immune cells, and Il-6, adiponectin and irisin, which have anti-inflammatory effects, continued to be significantly and positively modified, 8 months post-intervention. These data demonstrated for the first time, that c-miRNA correlations with metabolic parameters and insulin sensitivity are in fact only indirect and likely associated with the level systemic inflammation. More generally speaking, this important result explains the high variability between the previous studies designed to identify specific c-miRNAs associated with the severity of insulin-resistance. The results of all these studies should take into account the level of inflammation of the patients. In addition, this finding could also explain why, whatever the pathology considered (i.e.; cancers, diabetes, neurodegenerative disorders, inflammatory diseases) the same subset of miRNAs is always found altered in the blood of patients vs healthy subjects, as these pathologies are all associated with the development of inflammation.
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Inflamación/sangre , Resistencia a la Insulina , MicroARNs/sangre , Obesidad/sangre , Estado Prediabético/sangre , Circunferencia de la Cintura , Adulto , Antropometría , Pueblo Asiatico , Glucemia/análisis , Citocinas/metabolismo , Ejercicio Físico , Ayuno , Femenino , Humanos , Insulina/metabolismo , Estilo de Vida , Masculino , Persona de Mediana Edad , Ciencias de la Nutrición , Obesidad/fisiopatología , Estado Prediabético/fisiopatología , SístoleRESUMEN
BACKGROUND: Cerebral palsy (CP) associates cerebral function damages with strong locomotor defects and premature sarcopenia. We previously showed that fibroblast growth factor 19 (FGF19) exerts hypertrophic effects on skeletal muscle and improves muscle mass and strength in mouse models with muscle atrophy. Facing the lack of therapeutics to treat locomotor dysfunctions in CP, we investigated whether FGF19 treatment could have beneficial effects in an experimental rat model of CP. METHODS: Cerebral palsy was induced in male Wistar rat pups by perinatal anoxia immediately after birth and by sensorimotor restriction of hind paws maintained until Day 28. Daily subcutaneous injections with recombinant human FGF19 (0.1 mg/kg bw) were performed from Days 22 to 28. Locomotor activity and muscle strength were assessed before and after FGF19 treatment. At Day 29, motor coordination on rotarod and various musculoskeletal parameters (weight of tibia bone and of soleus and extensor digitorum longus (EDL) muscles; area of skeletal muscle fibres) were evaluated. In addition, expression of specific genes linked to human CP was measured in rat skeletal muscles. RESULTS: Compared to controls, CP rats had reduced locomotion activity (-37.8% of distance travelled, P < 0.05), motor coordination (-88.9% latency of falls on rotarod, P < 0.05) and muscle strength (-25.1%, P < 0.05). These defects were associated with reduction in soleus (-51.5%, P < 0.05) and EDL (-42.5%, P < 0.05) weight, smaller area of muscle fibres, and with lower tibia weight (-38%, P < 0.05). In muscles from rats submitted to CP, changes in the expression levels of several genes related to muscle development and neuromuscular junctions were similar to those found in wrist muscle of children with CP (increased mRNA levels of Igfbp5, Kcnn3, Gdf8, and MyH4 and decreased expression of Myog, Ucp2 and Lpl). Compared with vehicle-treated CP rats, FGF19 administration improved locomotor activity (+53.2%, P < 0.05) and muscle strength (+25.7%, P < 0.05), and increased tibia weight (+13.8%, P < 0.05) and soleus and EDL muscle weight (+28.6% and +27.3%, respectively, P < 0.05). In addition, it reduced a number of very small fibres in both muscles (P < 0.05). Finally, gene expression analyses revealed that FGF19 might counteract the immature state of skeletal muscles induced by CP. CONCLUSIONS: These results demonstrate that pharmacological intervention with recombinant FGF19 could restore musculoskeletal and locomotor dysfunction in an experimental CP model, suggesting that FGF19 may represent a potential therapeutic strategy to combat the locomotor disorders associated with CP.
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Parálisis Cerebral , Animales , Parálisis Cerebral/tratamiento farmacológico , Femenino , Factores de Crecimiento de Fibroblastos , Locomoción , Masculino , Ratones , Músculo Esquelético , Embarazo , Ratas , Ratas Wistar , Canales de Potasio de Pequeña Conductancia Activados por el CalcioRESUMEN
The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.
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Tejido Adiposo Blanco/metabolismo , Antígeno B7-H1/biosíntesis , Regulación de la Expresión Génica , Células Madre Mesenquimatosas/citología , Obesidad/metabolismo , Linfocitos T/inmunología , Animales , COVID-19/inmunología , Diferenciación Celular , Técnicas de Cocultivo , Humanos , Inmunohistoquímica , Inflamación , Interferón gamma/metabolismo , Leucocitos Mononucleares/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/inmunología , SARS-CoV-2 , Linfocitos T/citologíaRESUMEN
Postmenopausal women represent a vulnerable population towards endocrine disruptors due to hormonal deficit. We previously demonstrated that chronic exposure of ovariectomized C57Bl6/J mice fed a high-fat, high-sucrose diet to a low-dose mixture of chemicals with one dioxin, one polychlorobiphenyl, one phthalate, and bisphenol A triggered metabolic alterations in the liver but the intestine was not explored. Yet, the gastrointestinal tract is the main route by which pollutants enter the body. In the present study, we investigated the metabolic consequences of ovarian withdrawal and E2 replacement on the various gut segments along with investigating the impact of the mixture of pollutants. We showed that genes encoding estrogen receptors (Esr1, Gper1 not Esr2), xenobiotic processing genes (e.g., Cyp3a11, Cyp2b10), and genes related to gut homeostasis in the jejunum (e.g., Cd36, Got2, Mmp7) and to bile acid biosynthesis in the gut (e.g., Fgf15, Slc10a2) and liver (e.g., Abcb11, Slc10a1) were under estrogen regulation. Exposure to pollutants mimicked some of the effects of E2 replacement, particularly in the ileum (e.g., Esr1, Nr1c1) suggesting that the mixture had estrogen-mimetic activities. The present findings have important implications for the understanding of estrogen-dependent metabolic alterations with regards to situations of loss of estrogens as observed after menopause.
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Contaminantes Ambientales , Animales , Dieta Alta en Grasa , Contaminantes Ambientales/toxicidad , Estradiol , Estrógenos , Femenino , Humanos , Hígado , Ratones , Ratones Endogámicos C57BL , OvariectomíaRESUMEN
Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, it is well accepted that the gut plays an important role. To gain more insights into the mechanisms occurring in the different regions of the intestine, adult male mice were fed a high-fat-high sucrose (HFS) diet for 8 days and treated with metformin by gavage (300 mg/day/kg body weight) during the HFS diet. Metformin counteracted HFS diet-induced overexpression of a network of genes involved in the transport of glucose and fatty acids in the different regions of the small intestine. It also induced beneficial modification of secondary bile acid profile in the caecum, with a reduction of deoxycholic acid and lithocholic acid levels and increased abundance of ursodeoxycholic acid and tauroursodeoxycholic acid, potentially leading to FRX inhibition. In parallel, metformin treatment was associated with specific changes of the microbiota composition in the lumen of the different regions of the intestine. Metformin induced a marked increase in the abundance of Akkermansia muciniphila in the lumen all along the gut and counteracted the effects of HFS diet on the abundances of some bacterial groups generally associated with metabolic disturbances (f-Lachnospiraceae, f-Petostreptococcaceae, g-Clostidium). Therefore, the present work clearly emphasises the role of all the regions of the intestinal tract in the beneficial action of the antidiabetic drug metformin in a prediabetic mouse model.
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Dieta de Carga de Carbohidratos/efectos adversos , Sacarosa en la Dieta/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Hipoglucemiantes/farmacología , Mucosa Intestinal/efectos de los fármacos , Metformina/farmacología , Animales , Hipoglucemiantes/uso terapéutico , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Masculino , Metformina/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/etiología , Estado Prediabético/metabolismo , Estado Prediabético/microbiologíaRESUMEN
This study aimed to evaluate the effects of ingestion of live (9 log CFU mL-1) and ultrasound-inactivated (paraprobiotic, 20 kHz, 40 min) Lacticaseibacillus casei 01 cells for 28 days on healthy parameters (biochemical and cardiovascular) and intestinal microbiota (amplicon sequencing of 16S ribosomal RNA) of rats fed a high-fat diet. Twenty-four male Wistar rats were divided into four groups of six animals: CTL (standard diet), HFD (high-fat diet), HFD-LC (high-fat diet and live L. casei), and HFD-ILC (high-fat diet and inactivated L. casei). The administration of live and ultrasound-inactivated L. casei prevented the increase (p < 0.05) in cholesterol levels (total and LDL) and controlled the insulin resistance in rats fed a high-fat diet. Furthermore, it promoted a modulation of the intestinal microbial composition by increasing (p < 0.05) beneficial bacteria (Lachnospiraceae and Ruminoccocaceae) and decreasing (p < 0.05) harmful bacteria (Clostridiaceae, Enterobacteriaceae, and Helicobacteriacea), attenuating the effects promoted by the HFD ingestion. Only live cells could increase (p < 0.05) the HDL-cholesterol, while only inactivated cells caused attenuation (p < 0.05) of the blood pressure. Results show beneficial effects of live and inactivated L. casei 01 and indicate that ultrasound inactivation produces a paraprobiotic with similar or improved health properties compared to live cells.
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Sistema Cardiovascular , Dieta Alta en Grasa/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Lactobacillaceae/fisiología , Lactobacillaceae/efectos de la radiación , Ondas Ultrasónicas , Animales , Bacterias/clasificación , Bacterias/genética , Peso Corporal , Ingestión de Alimentos , Microbioma Gastrointestinal/genética , Resistencia a la Insulina , Intestinos/microbiología , Masculino , Probióticos/farmacología , ARN Ribosómico 16S , Ratas , Ratas WistarRESUMEN
Mesenchymal stem cells from healthy adipose tissue are adipocytes progenitors with immunosuppressive potential that are used for years in cell therapy. Whether adipose stem cells (ASC) may prevent inflammation in early obesity is not known. To address this question, we performed a kinetic study of high-fat (HF) diet induced obesity in mice to follow the immune regulating functions of adipose stem cells (ASC) isolated from the subcutaneous (SAT) and the visceral adipose tissue (VAT). Our results show that, early in obesity and before inflammation was detected, HF diet durably and differently activated ASC from SAT and VAT. Subcutaneous ASC from HF-fed mice strongly inhibited the proliferation of activated T lymphocytes, whereas visceral ASC selectively inhibited TNFα expression by macrophages and simultaneously released higher concentrations of IL6. These depot specific differences may contribute to the low-grade inflammation that develops with obesity in VAT while inflammation in SAT is delayed. The mechanisms involved differ from those already described for naïve cells activation with inflammatory cytokines and probably engaged metabolic activation. These results evidence that adipose stem cells are metabolic sensors acquiring an obesity-primed immunocompetent state in answer to depot-specific intrinsic features with overnutrition, placing these cells ahead of inflammation in the local dialog with immune cells.
Asunto(s)
Tejido Adiposo/inmunología , Inflamación/inmunología , Grasa Intraabdominal/inmunología , Células Madre Mesenquimatosas/inmunología , Obesidad/fisiopatología , Grasa Subcutánea/inmunología , Linfocitos T/inmunología , Tejido Adiposo/patología , Animales , Inflamación/patología , Grasa Intraabdominal/patología , Activación de Linfocitos , Masculino , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos C57BL , Grasa Subcutánea/patología , Linfocitos T/patologíaRESUMEN
BACKGROUNDHigh circulating levels of ceramides (Cer) and sphingomyelins (SM) are associated with cardiometabolic diseases. The consumption of whole fat dairy products, naturally containing such polar lipids (PL), is associated with health benefits, but the impact on sphingolipidome remains unknown.METHODSIn a 4-week randomized controlled trial, 58 postmenopausal women daily consumed milk PL-enriched cream cheese (0, 3, or 5 g of milk PL). Postprandial metabolic explorations were performed before and after supplementation. Analyses included SM and Cer species in serum, chylomicrons, and feces. The ileal contents of 4 ileostomy patients were also explored after acute milk PL intake.RESULTSMilk PL decreased serum atherogenic C24:1 Cer, C16:1 SM, and C18:1 SM species (Pgroup < 0.05). Changes in serum C16+18 SM species were positively correlated with the reduction of cholesterol (r = 0.706), LDL-C (r = 0.666), and ApoB (r = 0.705) (P < 0.001). Milk PL decreased chylomicron content in total SM and C24:1 Cer (Pgroup < 0.001), parallel to a marked increase in total Cer in feces (Pgroup < 0.001). Milk PL modulated some specific SM and Cer species in both ileal efflux and feces, suggesting differential absorption and metabolization processes in the gut.CONCLUSIONMilk PL supplementation decreased atherogenic SM and Cer species associated with the improvement of cardiovascular risk markers. Our findings bring insights on sphingolipid metabolism in the gut, especially Cer, as signaling molecules potentially participating in the beneficial effects of milk PL.TRIAL REGISTRATIONClinicalTrials.gov, NCT02099032, NCT02146339.FUNDINGANR-11-ALID-007-01; PHRCI-2014: VALOBAB, no. 14-007; CNIEL; GLN 2018-11-07; HCL (sponsor).